Rapid and validated fluorometric HPLC method for determination of gabapentin in human plasma and urine for clinical application.

WHAT IS KNOWN AND OBJECTIVE: A rapid derivatization and validated HPLC method for gabapentin in human plasma and urine is needed for clinical use. The objective of this study was to establish a rapid and validated analytical method for the determination of gabapentin in human plasma and urine using isocratic fluorometric HPLC for clinical application. METHODS: This analytical method is based on precolumn fluorescent derivatization using 4-fluoro-7-nitro-benzofurazan. The derivatization was coupled to fast HPLC separation using a 2·3 µm-particle size ODS column (100 × 4·6 mm i.d.). RESULTS AND DISCUSSION: The derivatization of gabapentin was optimized and HPLC separation was achieved over an ODS column with a run time of 3·5 min. Calibration curves in human plasma and urine were linear over the concentration ranges of 0·05-10 and 10-1000 µg/mL, respectively. Intra- and inter-assay precision and accuracy values of plasma were within 8·0% and 101-109% and within 8·3% and 94-108%, respectively. Those of urine were within 8·5% and 97-106% and within 9·5% and 97-105%, respectively. This validated method was applied to a pharmacokinetic study in healthy subjects. Interindividual variations in plasma disposition and urinary excretion of gabapentin were observed. WHAT IS NEW AND CONCLUSION: A rapid and validated isocratic fluorometric HPLC method for the determination of gabapentin in human plasma and urine for clinical application has been established. This method can be utilized to evaluate the pharmacokinetic disposition of gabapentin in humans.

Effective plasma concentrations of mycophenolic acid and its glucuronide in systemic lupus erythematosus patients in the remission-maintenance phase.

WHAT IS KNOWN AND OBJECTIVE: Mycophenolate mofetil (MMF) has been reported recently to be effective in the treatment of systemic lupus erythematosus (SLE). The therapeutic range of mycophenolic acid (MPA) in SLE in the remission-maintenance phase remains to be clarified. The aim of this study was to evaluate the therapeutic efficacy of MMF and predose plasma concentrations of MPA and its phenolic glucuronide (MPAG) in patients with SLE in the remission-maintenance phase. METHODS: Thirty-one patients with SLE receiving a fixed dosage regimen of MMF (median and interquartile range, 1500 and 1000-2000mg/day) for at least 1month and who had not experienced any adverse drug reactions for more than 3months were enrolled. RESULTS: Significant improvement was observed after MMF administration in total haemolytic complement CH(50) and its fractions C3 and C4, immunoglobulins IgG, IgA and IgM, anti-dsDNA antibody, serum concentration of albumin and red blood cell count, even though the mean daily dose of prednisolone was significantly reduced (P=0·02). Median predose plasma concentrations of MPA and MPAG were 1·95 and 26·2µg/mL (interquartile ranges, 0·94-2·96 and 18·6-53·7 µg/mL). Predose plasma concentrations of MPA and MPAG correlated significantly with MMF dose (r=0·64, P<0·01 and r=0·39, P=0·03). WHAT IS NEW AND CONCLUSIONS: MMF improved clinical laboratory markers and reduced prednisolone dosage in SLE patients with predose plasma concentration of MPA and MPAG in the interquartile ranges of 0·94-2·96 and 18·6-53·7µg/mL, respectively.

Cyclosporine alters correlation between free and total mycophenolic acid in kidney transplant recipients in the initial phase.

WHAT IS KNOWN AND OBJECTIVE: The factors affecting the pharmacokinetics of free mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) are still unclear. The aim of this study was to evaluate the influence of cyclosporine on the pharmacokinetics of free MPA and MPAG. METHODS: Seventy-seven kidney transplant recipients (23 were in an initial phase and 54 in a stable phase; 41 were treated with cyclosporine and 36 with tacrolimus) were enrolled. Free and total MPA and MPAG were determined using HPLC. The correlations between free and total predose concentrations (C(0) ) of MPA or MPAG were evaluated separately in patients receiving calcineurin inhibitor medications. RESULTS AND DISCUSSION: Serum concentration of albumin was lower in the initial phase than in the stable phase. A higher ratio of free MPAG C(0) to free MPA C(0) was observed in cyclosporine-treated than tacrolimus-treated kidney transplant recipients. Free MPA C(0) correlated weakly with total MPA C(0) in kidney transplant recipients treated with cyclosporine in the initial phase (ρ= 0·53, P = 0·06). WHAT IS NEW AND CONCLUSION: Cyclosporine increased the ratio of free MPAG C(0) to free MPA C(0) and varied the free fraction of MPA in the hypoalbuminaemic kidney transplant recipients in the initial phase.

Validated LC coupled to ESI-MS/MS analysis for fentanyl in human plasma and UV analysis in applied reservoir transdermal patches using a simple and rapid procedure.

BACKGROUND AND OBJECTIVES: Fentanyl has been used for cancer pain in transdermal formulation. The aim of the present study was to establish an analytical method for fentanyl in human plasma and in an applied transdermal reservoir patch (Reservoir-TTS), as well as for therapeutic monitoring of fentanyl in cancer patients. METHOD: Electro-spray ionization mass spectrometric (ESI-MS/MS) analysis followed solid phase extraction (SPE) from human plasma and drug reservoir extraction from an applied Reservoir-TTS. Each separation was completed within 9 min using an ODS column (particle size, 3 microm, 2.0 mm i.d. x 75 mm) with 25% acetonitrile containing 5 mm ammonium acetate at pH 3.5. In the ESI-MS/MS analysis, the calibration curve for fentanyl was linear over a concentration range of 0.05-7.2 ng/mL in human plasma. The extraction efficiency of fentanyl in the human plasma was more than 95%. The intra- and interassay precision and accuracy were within 7% and 97.3-101.2%, respectively. The lower LOQ for fentanyl was 0.05 ng/mL in the human plasma. The extraction of the 25 microg/h and 50 microg/h Reservoir-TTS gave reproducible recoveries of 88.3% and 90.9%, respectively. The plasma concentration of fentanyl showed large interindividual variation in 31 patients with cancer pain. CONCLUSION: The method described is simple, accurate, and reproducible, and should be helpful for the therapeutic monitoring of fentanyl in cancer patients.

Effect of arachnoid plasty using fibrin glue membrane after clipping of ruptured aneurysm on the occurrence of complications and outcome in the elderly patients.

BACKGROUND: In elderly patients with aneurysmal subarachnoid hemorrhage (SAH), complications including vasosopasm, subdural effusion, and late hydrocephalus, are liable to occur even after aneurysmal surgery. We examined prospectively the efficacy of arachnoid plasty using fibrin glue membrane during surgery of ruptured aneurysms in the elderly patients for preventing complications. The effects on the modified Rankin scale (mRS) and the Glasgow outcome scale (GOS) 3 months after SAH were noted. METHODS: Total of 31 patients aged more than 70 years selected from a consecutive series of patients with aneurysmal SAH, were divided into two groups alternately, a group with arachnoid plasty (n = 16) and a control group without arachnoid plasty (n = 15). Statistical analyses were performed to assess relationships among various clinical and neuroradiological variables, especially between arachnoid plasty and occurrence of symptomatic vasospasm, subdural effusion, late hydrocephalus, or outcome such as mRS and GOS 3 months after onset. FINDINGS: Statistical analyses revealed that arachnoid plasty were associated with late hydrocephalus and subdural effusion negatively, but with better mRS at 3 months after SAH. A tendency to be associated with less frequent symptomatic vasospasm was also noted. CONCLUSION: Arachnoid plasty using fibrin glue is suggested to be effective in preventing complications associated with SAH and aneurysmal surgery. A better outcome in the elderly patients can be achieved.

A new, iterative strategy of oligosaccharide synthesis based on highly reactive beta-bromoglycosides derived from selenoglycosides.

Stereoselective conversion of a selenoglycoside to a beta-bromoglycoside in the absence of a glycosyl acceptor followed by the coupling with another selenoglycoside affords the corresponding glycosylated selenoglycoside, which could be directly used for the next glycosylation. The iteration of this sequence allows the synthesis of a variety of oligosaccharides including an elicitor active heptasaccharide. [reaction: see text]

[Causal inference in medicine--decision making].

In the field of occupational medicine, either when we consider some preventive plans or when we make decisions to compensate for occupational diseases, it has been necessary to discuss causality between work and disease. Furthermore, epidemiologic causality has recently been used in risk assessment in occupational and environmental settings. We have shown that the law of causality in medicine is recognized as probability and continuous variables. Such a law of causality has been recognized in the same way as probability in physics, too, and has been regarded as a model of science. Physicists and mathematicians had claimed the importance of probability in causal inference as well as the principle of uncertainty before it was discovered. We, then, explained Etiologic Fraction (EF), Attributable Proportion for the Exposed Population (APE), Probability of Causation (PC), and so on. The PC has been used to ascertain the conditional probability in an individual case of a disease having been caused by a particular prior exposure, by using the experience of exposed populations to determine the appropriate relative risk, and this has been used for compensation for exposed cases. Next the applicability of information from a population to individuals was presented. Third, we provided a brief historical aspect of epidemiology. The evolutions in Epidemiology have been very rapid, so we pointed out that, in Japan, we could observe many incommensurable phenomena in epidemiologists and physicians depending on the era which was studied by them. Fourth, we discussed judgement and political application based on epidemiologic evidence, using Yanagimoto's classification is also taken or not should be estimated and compared. We presented several examples of reasoning in judgements. Lastly, we discussed several tasks and assignments for the future of epidemiology.

Effects of a one-hour educational program on medical students' attitudes to mental illness.

A new 1-h educational program was developed to change attitudes towards mental illness, and was conducted on 95 first-year medical students in order to investigate its effects on their attitudes towards mental illness, using a pre- and postquestionnaire study design. A similar study without the program was conducted on 94 first-year medical students as controls. After the program, more students replied that they would accept former patients on relatively close social distance items. Favorable attitudinal changes were observed in terms of 'psychiatric services', 'human rights of the mentally ill', 'patients' independence in social life', and 'cause and characteristics of mental illness'. In contrast, no significant change was observed in the control group. These results suggest that attitudes towards mental illness could be changed favorably by this program.

Possible remediation of dioxin-polluted soil by steam distillation.

2,7-Dichlorodibenzo-p-dioxin (DCDD) was found to evaporate easily with water vapor from a heated solution. Steam distillation was also effective for the removal of DCDD from DCDD-applied soil; its concentration (250 microg/50g soil) in the original soil decreased to less than 5% after steam distillation for only 20 min. Actual dioxin-polluted soil in Tokorozawa City was partially decontaminated using the same method. These results suggest that steam distillation could be a new remedial method for soils contaminated with persistent environmental pollutants, such as dioxins and polychlorinated biphenyls.

Smoking and mental health: cross-sectional and cohort studies in an occupational setting in Japan.

BACKGROUND: The relationship between smoking and mental health remains unclear. METHODS: We carried out a cross-sectional study and a cohort study on the possible association of smoking and mental health in 782 workers. Using a questionnaire including the 30-item General Health Questionnaire (GHQ-30) and items related to the smoking state, the association between smoking and mental health was evaluated separately in males and females. The subjects were classified into smokers and nonsmokers, and changes in the GHQ score during a 2-year follow-up period were evaluated. To control potential confounding factors, multiple regression analyses were performed. RESULTS: The cross-sectional study showed no difference in the GHQ score between smokers and nonsmokers among males but a significantly higher GHQ score for smokers than nonsmokers among females. This difference among females was confirmed to be significant by multiple regression analysis. The 2-year cohort study showed a decrease in the GHQ score in each group and no reduction in the difference in the GHQ score between smokers and nonsmokers among females. CONCLUSIONS: No difference was observed in mental health between smokers and nonsmokers in males. However, in females, smokers showed poorer mental health than nonsmokers, and this difference remained unchanged even after 2 years.

Expressed emotion of families and the course of mood disorders: a cohort study in Japan.

BACKGROUND: Findings on expressed emotion (EE) of the family and the course of mood disorders have not been consistent. There has also been no report on these problems from Asia. METHODS: The subjects were 32 patients diagnosed to have mood disorders on the basis of DSM-IV and ICD-10 and 36 principal members of their families. EE was evaluated using Camberwell Family Interview (CFI). A cohort study was conducted for 9 months after discharge of the patients. The patients were divided into a high-EE group and a low-EE group using a few cut-off points concerning the number of critical comments (CCs) and emotional over-involvement (EOI), the 9-month relapse risks were compared, and the relapse risk ratio and its 95% confidence interval were calculated. Also, the sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and the optimal cut-off point was evaluated. Multiple logistic regression analysis was performed to control the effects of potential confounding factors. RESULTS: When the subjects with three or more CCs, or an EOI score of three or higher were regarded as a high-EE group, and the others as a low-EE group, the nine-month relapse risks were 83.3% (5/6) and 19.2% (5/26), respectively, and the relapse risk ratio (95% confidence interval) was 4.3 (1.8-12.2). The values of the validity parameters were the highest with these cut-off points. The effect of EE was also significant on multiple logistic regression analysis. LIMITATIONS: Small sample size and severity of the patients. CONCLUSIONS: Families' EE based on CFI correlated with relapse also in Japan.

A case-control study of the relationships among silica exposure, gastric cancer, and esophageal cancer.

BACKGROUND: We examined the effect of silica exposure on gastric and esophageal cancer mortality using a cancer control series in a population setting. METHODS: Cases and controls were restricted to male subjects and were drawn from death certificates in the Tobi area of Japan. A control group was selected from a series of deaths due to colon cancer, and cancers of other organs. The Japanese death certificate system is comprehensive because all deaths must be reported to the local office and death certificates are written by medical doctors. Age and smoking habits adjusted the Mantel-Haenszel odds ratios were estimated. RESULTS: For gastric cancer, the age-, smoking-adjusted odds ratios were 1.22 (95% CI 0.74-2.01) for colon cancer and the other cancer control for silica exposure work, and 1. 36 (95% CI 0.76-2.43) for silicosis. For esophageal cancer, the age- and smoking-adjusted odds ratios were 1.53 (95% CI 0.59-3.96) for the cancer control for silica exposure, and 2.33 (95% CI 0.87-6.23) for silicosis, respectively. CONCLUSIONS: The results suggest that gastric and esophageal cancer were related to silica exposure and silicosis in the study area, although they did not reach a statistically significant level because of the small sample size. The estimated odds ratios were higher for esophageal cancer and silicotic patients.

Expressed emotion and psychoeducational intervention for relatives of patients with schizophrenia: a randomized controlled study in Japan.

The benefit of single-family treatment (SFT) in addition to short educational sessions (SES) consisting of multiple-family treatment was investigated. The study design was a randomized controlled study. Subjects were 30 patients suffering from schizophrenia with at least one of their family members showing high expressed emotion (EE) in the Camberwell Family Interview. After the SES, the patients were randomly allocated to two groups: those who received routine individual outpatient treatment and those who received additional SFT and routine treatment. The two groups were followed for 9 months after discharge, and the relapse risks were compared. The relapse risk was lower in the SES+SFT group than in the SES group (23.1% vs. 35.3%). However, the difference was not significant. When high-EE families were classified into those with many critical comments (high-CC) or a high score of emotional overinvolvement (high-EOI), the relapse risk was 0% in the patients living with a high-CC family not only in the SES+SFT group but also in SES group. In the patients living with a high-EOI family, the relapse risk was lower in the SES+SFT group than in the SES group (42.9% vs. 60.0%). These findings suggest that high-EE families should receive at least SES, and additional SFT should be given to families with specific needs.

Expressed emotion and family distress in relatives of patients with schizophrenia in Japan.

We evaluated the association between distress and expressed emotion (EE) in family members of patients with schizophrenia by the General Health Questionnaire (GHQ), the Camberwell Family Interview (CFI), and the Five-Minute Speech Sample (FMSS). The GHQ score was higher in the high-EE group determined by both the CFI and FMSS. The difference in the GHQ score between high-EE and low-EE groups was more marked for the CFI. Family distress is closely associated with the EE classification, but the EE classification by the CFI more markedly reflected family distress versus the FMSS. Even in relatives with low EE, distress was marked, and therefore, coping with mental health in family members is important.

[Achievement of causal inference in the social medicine in Japan].

As a condition to achieving an agreement of recognition on the causal relationship in medicine, we firstly explained Hume's problem and counterfactual model. We, however, emphasized that we believe in the existence of causality on medical issues in our daily lives. Therefore, we illustrated conditions when we usually believe in causality. On the other hand, we criticized two well-known key phrases, "lack of mechanism in epidemiology" and "black box in epidemiology", which have often been used in Japan for skeptic viewpoints against epidemiologic methods even if epidemiology is often used to elucidate a causal effect in medicine in the world. We emphasized that a priori determinations of levels for inference of mechanism is necessary. And, the level and feature of mechanism should be defined in concrete expressions. After explanation of these basic concepts, we mentioned a classic view on specific diseases and non-specific diseases which have not been sufficiently discussed enough yet in Japan. As an example, we used the statements in the Japanese Compensation Law for the Health Effect by Environmental Pollution. In Japan, the classification of these diseases has been confused with that between manifestational criteria of diseases and causal criteria of them. We described the basic concepts to illustrate the causal relationship between non-specific disease and its exposure by using attached figures. Actually, we cannot recognize disease occurrence as a specific disease for several reasons. We indicated that we can recognize the magnitude of effect by causal relationships in medicine as a quantitative continuous variable.

Effects of medical education on attitudes towards mental illness among medical students: a five-year follow-up study.

In order to clarify the effects of medical education on attitudes towards mental illness among medical students, a follow-up study was conducted. All 100 students entering Kochi Medical School in 1988 were subjects. The initial questionnaire survey was conducted in 1988, and followed up in 1993. Response rate was 69% in the initial survey, and 83% in the follow-up study. By the time of the follow-up, all of the students had completed their medical education, including courses in psychiatry and mental health. Results were as follows: At the follow-up study, 1) a significantly higher percentage of students replied that they accepted the mentally ill as co-workers; 2) significantly favorable changes were observed in attitudes towards psychiatric services; 3) optimism about the effectiveness of treatment for mental illness at an early stage and prevention of mental illness had decreased; and 4) no change was observed in attitudes toward human rights of the mentally ill, except in the case of one item stating that the mentally ill should not have children in order to avoid hereditary handicaps, with which a lower percentage agreed. Conclusively, medical education can play an important role in attitudes towards mental illness.

Effects of perceived job stress on mental health. A longitudinal survey in a Japanese electronics company.

We conducted a cohort study for 2 years to examine the causal relationship between perceived job stress and mental health. Questionnaire surveys, including a 30-item General Health Questionnaire (GHQ) and a questionnaire on perceived job stress were carried out every 6 months for 2 years. To clarify the causal relationship between job stress and mental health, we followed a group of workers who initially had a GHQ score < or = 7. Out of 462 workers who were thought to be in a healthy mental state, 282 were successfully followed for 2 years. We considered subjects who developed unhealthy mental health states (GHQ score > or = 8) as hazardous cases. To control potential confounding factors, proportional hazard analysis was done. The overall proportion hazardous cases detected in the development of an unhealthy mental health state over two years was 55.7%. Using Cox's proportional hazard model, workers who complained of perceived job stress had a greater hazard than those without job stress. In particular, the item 'poor relationship with superior' showed the largest adjusted hazard ratio [95% confidence interval (CI)] of 1.51 (1.06-2.15). The item 'too much trouble at work' also had a significant hazardous effect on mental health with an adjusted hazard ratio (95% CI) of 1.43 (1.00-2.04). Some specific items of perceived job stress could cause mental ill health in workers.

Evaluation of expressed emotion (EE) status in mood disorders in japan: inter-rater reliability and characteristics of EE.

The reliability of expressed emotion (EE) ratings by the Camberwell Family Interview (CFI) and characteristics of EE were evaluated in families of patients with mood disorders in Japan. The subjects were 27 patients with mood disorders and 31 members of their families. The CFI was carried out with the family members. EE was rated by two raters independently, and the inter-rater reliability was evaluated according to Spearman's correlation coefficient by ranks and the kappa-value. The distribution of subscales of EE in these subjects was compared with that in families of patients with schizophrenia in Japan and families of patients with mood disorders abroad. Concerning critical comments (CC), hostility (H), and emotional over-involvement (EOI), which are important for EE rating, Spearman's correlation coefficient and the kappa-values were 0.4-0.8, and the reliability of EE ratings in mood disorders was not high. The proportion of positive agreement was particularly low in H and EOI. CCs were fewer in families of Japanese patients with mood disorders than in those with schizophrenia or families of American or European patients with mood disorders. Re-evaluation of the inter-rater reliability of EE ratings in mood disorders is needed. Expressed emotion was more suppressed in families of patients with mood disorders than in those of patients with schizophrenia. Expressed emotion was also more reserved in the Japanese subjects than in their Western counterparts.

Seasonality of birth in patients with mood disorders in Japan.

BACKGROUND: Findings about seasonality of birth in individuals with mood disorders have been inconsistent. METHODS: Data were collected from the governmental statistics, the Patient Survey in Japan in 1996. The number of patients with mood disorders was 13,969. We obtained information about each patient's date of birth, sex, and diagnosis according to ICD-10. Distributions of monthly birth numbers of patients with mood disorders were compared to those of the general population. RESULTS: Birth excess was observed from winter to early-spring in both sexes, compared to births of the general population. The magnitude of the excess was larger in females than in males. Although the same tendencies were observed in patients with bipolar disorder and depressive disorder, the differences were more marked in females. LIMITATIONS: Insufficient birth data in the general population before 1940 and hospital diagnosis. CONCLUSION: Among Japanese patients with mood disorders, there are excess births from winter to early-spring, compared to the general population. This difference is more marked in females than in males.

Does smoking cessation improve mental health?

There is a possibility that cessation of smoking improves mental health, but there are no studies that have demonstrated this. A cohort study was performed for 1 year in 18 males who spontaneously stopped smoking (cessation group) and 173 who continued to smoke (smoking group). The mental health state was evaluated using the Japanese version of the 30-item General Health Questionnaire (GHQ-30) before the cessation of smoking and 6 months and 1 year after smoking cessation. Changes in the GHQ score were compared between the cessation and smoking groups. In order to control the effects of confounding factors, multiple regression analyses were performed using the GHQ score after 6 months and 1 year as dependent variables. The GHQ score in the cessation group significantly decreased 6 months and 1 year after smoking cessation (P < 0.04 and 0.01, respectively, by paired t-test). In the smoking group, the GHQ score slightly decreased. Repeated measure analysis of variance revealed that the decrease in the GHQ score in the cessation group was significantly larger than in the smoking group. Multiple regression analysis revealed significant effects of smoking cessation on mental health after controlling for other confounding factors. It can be concluded that smoking cessation may improve mental health.